Infections are an important cause of morbidity and mortality in patients with diabetes and stress-related hyperlgycemia. In healthy individuals, glucose levels in blood (~100 mg/dL) contrast sharply with those in the nasopharnyx (undetectable) and in the lower airways (<7 mg/dL). Diabetes, medical or surgical stress, and respiratory viral infections lead to elevated glucose levels in each of these compartments. Elevated blood glucose levels are known to impair antibacterial activities associated with phagocytes and other immune factors. However, the direct effects of hyperglycemia on the regulation of bacterial virulence have received little attention. In this regard, the Gram-positive pathogen Streptococcus pneumoniae serves as a useful and relevant model, as: 1) diabetes and other hyperglycemic conditions lead to increased risk from pneumococcal infections; 2) glucose regulates the expression of virulence factors important in the transition of S. pneumoniae from a colonizer of the nasopharnyx to an invasive pathogen; and 3) identical mechanisms for glucosemediated regulation are present in many Gram-positive bacteria. We found that glucose represses the expression of factors important for S. pneumoniae to colonize the nasopharynx, and increases expression of factors required for systemic virulence. Our hypothesis is that elevated levels of glucose in the bloodstream that lead to increased glucose in the nasopharynx enhance the transition from colonization to invasive disease. The specific aims are to determine the ability of S. pneumoniae to colonize and progress from the nasopharnyx to systemic sites in mouse models of: 1) type 1 diabetes, 2) type 2 diabetes, and 3) acute, transient hyperglycemia. In these studies, we will use Non-Obese Diabetic (NOD) and multiple low-dose Streptozotocin-treated mice as models for Type 1 diabetes; C57BL/6 mice fed a high fat diet as a model for Type 2 diabetes; and single high-dose streptozotocin-treated mice and bolus glucose injections as models for acute, transient hyperglycemia. Our studies will utilize the intranasal route of infection, thereby assessing the critical transition from colonization to invasion. Because other bacteria use similar mechanisms to respond to glucose, the results may have broad relevance for infections in hyperglycemic conditions.